Genetic variation in body weight and fatness in mice and humans is best explained by multigenic inheritance. Characterizing genetic involvement in the development of human obesity has been difficult due to lack of environmental and experimental control. Mouse models have proved to be a useful tool in the discovery of genes that influence body size because experimental control can be maintained over breeding and environment. The goal of this project is to identify genes and their alleles in mice that lead to variability in body weight, body length, and adipose depot weight, by tracking the co-segregation of genotypes with these phenotypes in an F2 intercross. Specific Aim l: Genome screen for markers that co-segregate with body weight, body length and adipose depot weight in an F2 intercross derived from the 129/) (129) and C57BL/6ByJ (B6) mouse strains: Hybrid mice from the 129 and B6 strains, phenotyped for body weight, body length and adipose depot weight, will be genotyped using polymorphic loci, and linkage analysis will be conducted to find regions influencing variation in these phenotypes. These strains were chosen for analysis because the 129 strain is lighter and leaner than the B6 strain, and large phenotypic variation exists within the F2 generation. Preliminary results from mouse chromosome 4 gave a LOD score of 8.8 near the leptin receptor gene (Lepr) for body weight, which accounts for approximately 15 percent of the genotypic variance. Specific Aim 2: Saturation genotyping of areas that give preliminary evidence for linkage. When areas of linkage are identified, the flanking regions will be densely genotyped to identify the 1-5 cM region most likely to contain the gene of interest. Specific Aim 3: Evaluation of candidate genes: identification of sequence variation and allele characterization: Candidate genes from the 129 and B6 strain will be sequenced to identify allelic variation that affects body weight, length and adipose depot weight. Mapping of chromosome 4 suggests previously unidentified alleles of Lepr may exist that lead to variation in body weight, body length and adipose depot weight in mice and therefore Lepr will be sequenced using DNA from B6 and 129 mice. Chromosome 2 also appears to contain a gene or genes that give evidence for linkage to body weight (LOD=4.8) and body length (LOD=3.6), and this region contains several candidate genes. The goal of this project is to understand how allelic variability affects body weight, body length, and adipose depot weight in the mouse. Orthologs of these genes may be involved in human obesity, and may have a significant impact on human health.